Pretreatment of Huoxue Jiedu Formula Ameliorates Myocardial Ischaemia/Reperfusion Injury by Decreasing Autophagy Via Activation of the PI3K/AKT/mTOR Pathway

Overview

Journal Front Pharmacol

Date 2021 Mar 15

PMID 33716739

Citations 3

Authors

Linzi Long

Zikai Yu

Shengjun Chen

Jiarui Wu

Yingying Liu

Jun Peng

Hua Qu

Changgeng Fu

Affiliations

Soon will be listed here.

Abstract

Myocardial ischaemia/reperfusion (I/R) results in myocardial injury via excessive autophagy. Huoxue Jiedu Formula (HJF) has been widely applied in China for the treatment of ischaemic heart disease. However, the mechanisms of HJF are still poorly understood. Thus, the present experiment was designed to observe the effects of HJF on myocardial I/R injury and explore the possible mechanism. Myocardial injury in rats subjected to myocardial I/R was reflected by nitrotetrazolium blue chloride staining, thioflavin S staining, serum creatine kinase-MB (CK-MB) and cardiac troponin T (cTnT). Autophagy was determined by electron microscopy, laser confocal microscopy, Q-PCR and western blot. The possible pathway was predicted by network pharmacology and validated and . Pretreatment of HJF decreased the no-reflow area, infarcted area, serum CK-MB levels and serum cTnT levels in I/R rat model. In addition, pretreatment of HJF decreased autophagy in heart tissues (decrease in Beclin-1 and LC3-II, and increase in Bcl-2, p62 and ratio of LC3-I/LC3-II). In the vivo study, pretreatment of HJF significantly decreased hypoxia/reoxygenation (H/R)-induced autophagy in H9C2 cells. Network pharmacology was applied to predict the possible mechanism by which HJF affects cardiac autophagy, and the PI3K/AKT/mTOR signalling pathway was the most significantly enriched pathway. And experimental studies demonstrated that pretreatment of HJF increased the phosphorylation of AKT and mTOR, and the effects of HJF on autophagy would be offset by PI3K inhibitor LY294002. Pretreatment of HJF ameliorates myocardial I/R injury by decreasing autophagy through activating PI3K/AKT/mTOR pathway.

Citing Articles

Recent advances of traditional Chinese medicine against cardiovascular disease: overview and potential mechanisms.

Dai J, Qiu L, Lu Y, Li M Front Endocrinol (Lausanne). 2024; 15:1366285.

PMID: 39403576 PMC: 11471557. DOI: 10.3389/fendo.2024.1366285.

Active components and molecular mechanisms of Sagacious Confucius' Pillow Elixir to treat cognitive impairment based on systems pharmacology.

Hou Z, Yang X, Jiang L, Song L, Li Y, Li D Aging (Albany NY). 2023; 15(14):7278-7307.

PMID: 37517091 PMC: 10415554. DOI: 10.18632/aging.204912.

Protective effect of HINT2 on mitochondrial function via repressing MCU complex activation attenuates cardiac microvascular ischemia-reperfusion injury.

Li S, Chen J, Liu M, Chen Y, Wu Y, Li Q Basic Res Cardiol. 2021; 116(1):65.

PMID: 34914018 PMC: 8677646. DOI: 10.1007/s00395-021-00905-4.

References

Bourke L, McDonnell T, McCormick J, Pericleous C, Ripoll V, Giles I . Antiphospholipid antibodies enhance rat neonatal cardiomyocyte apoptosis in an in vitro hypoxia/reoxygenation injury model via p38 MAPK. Cell Death Dis. 2017; 8(1):e2549. PMC: 5386347. DOI: 10.1038/cddis.2016.235. View

Wen J, Xu B, Sun Y, Lian M, Li Y, Lin Y . Paeoniflorin protects against intestinal ischemia/reperfusion by activating LKB1/AMPK and promoting autophagy. Pharmacol Res. 2019; 146:104308. DOI: 10.1016/j.phrs.2019.104308. View

Matsui Y, Takagi H, Qu X, Abdellatif M, Sakoda H, Asano T . Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ Res. 2007; 100(6):914-22. DOI: 10.1161/01.RES.0000261924.76669.36. View

Sadoshima J . The role of autophagy during ischemia/reperfusion. Autophagy. 2008; 4(4):402-3. DOI: 10.4161/auto.5924. View

Fan G, Yu J, Asare P, Wang L, Zhang H, Zhang B . Danshensu alleviates cardiac ischaemia/reperfusion injury by inhibiting autophagy and apoptosis via activation of mTOR signalling. J Cell Mol Med. 2016; 20(10):1908-19. PMC: 5020629. DOI: 10.1111/jcmm.12883. View

Gewirtz H, Dilsizian V . Myocardial Viability: Survival Mechanisms and Molecular Imaging Targets in Acute and Chronic Ischemia. Circ Res. 2017; 120(7):1197-1212. DOI: 10.1161/CIRCRESAHA.116.307898. View

Fan X, Wang J, Hou J, Lin C, Bensoussan A, Chang D . Berberine alleviates ox-LDL induced inflammatory factors by up-regulation of autophagy via AMPK/mTOR signaling pathway. J Transl Med. 2015; 13:92. PMC: 4365560. DOI: 10.1186/s12967-015-0450-z. View

Nishida K, Kyoi S, Yamaguchi O, Sadoshima J, Otsu K . The role of autophagy in the heart. Cell Death Differ. 2008; 16(1):31-8. DOI: 10.1038/cdd.2008.163. View

Yao T, Ying X, Zhao Y, Yuan A, He Q, Tong H . Vitamin D receptor activation protects against myocardial reperfusion injury through inhibition of apoptosis and modulation of autophagy. Antioxid Redox Signal. 2014; 22(8):633-50. PMC: 4346660. DOI: 10.1089/ars.2014.5887. View

10.

Zheng Y, Gu S, Li X, Tan J, Liu S, Jiang Y . Berbamine postconditioning protects the heart from ischemia/reperfusion injury through modulation of autophagy. Cell Death Dis. 2017; 8(2):e2577. PMC: 5386498. DOI: 10.1038/cddis.2017.7. View

11.

Jung C, Ro S, Cao J, Otto N, Kim D . mTOR regulation of autophagy. FEBS Lett. 2010; 584(7):1287-95. PMC: 2846630. DOI: 10.1016/j.febslet.2010.01.017. View

12.

Hausenloy D, Yellon D . Targeting Myocardial Reperfusion Injury--The Search Continues. N Engl J Med. 2015; 373(11):1073-5. DOI: 10.1056/NEJMe1509718. View

13.

Sciarretta S, Hariharan N, Monden Y, Zablocki D, Sadoshima J . Is autophagy in response to ischemia and reperfusion protective or detrimental for the heart?. Pediatr Cardiol. 2010; 32(3):275-81. PMC: 3261079. DOI: 10.1007/s00246-010-9855-x. View

14.

Wu S, Chang G, Gao L, Jiang D, Wang L, Li G . Trimetazidine protects against myocardial ischemia/reperfusion injury by inhibiting excessive autophagy. J Mol Med (Berl). 2018; 96(8):791-806. DOI: 10.1007/s00109-018-1664-3. View

15.

Jiang Y, Chang G, Wang Y, Zhang D, Cao L, Liu J . Geniposide Prevents Hypoxia/Reoxygenation-Induced Apoptosis in H9c2 Cells: Improvement of Mitochondrial Dysfunction and Activation of GLP-1R and the PI3K/AKT Signaling Pathway. Cell Physiol Biochem. 2016; 39(1):407-21. DOI: 10.1159/000445634. View

16.

Zhang Z, Li H, Chen S, Li Y, Cui Z, Ma J . Knockdown of MicroRNA-122 Protects H9c2 Cardiomyocytes from Hypoxia-Induced Apoptosis and Promotes Autophagy. Med Sci Monit. 2017; 23:4284-4290. PMC: 5597036. DOI: 10.12659/msm.902936. View

17.

Lekli I, Haines D, Balla G, Tosaki A . Autophagy: an adaptive physiological countermeasure to cellular senescence and ischaemia/reperfusion-associated cardiac arrhythmias. J Cell Mol Med. 2016; 21(6):1058-1072. PMC: 5431132. DOI: 10.1111/jcmm.13053. View

18.

Kroemer G, Levine B . Autophagic cell death: the story of a misnomer. Nat Rev Mol Cell Biol. 2008; 9(12):1004-10. PMC: 2727358. DOI: 10.1038/nrm2529. View

19.

Xu L, Shen J, Dai S, Sun L, Chen X . Tetramethylpyrazine Attenuated Sevoflurane-Induced Neurotoxicity by Enhancing Autophagy through GPR50/CREB Pathway in SH-SY5Y Cells. Am J Chin Med. 2020; 48(4):945-966. DOI: 10.1142/S0192415X20500457. View

20.

Nair A, Jacob S . A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm. 2016; 7(2):27-31. PMC: 4804402. DOI: 10.4103/0976-0105.177703. View